It has been noted throughout human history that women, upon reaching the age of memopause, have suffered from a variety of symptoms associated with the decline in ovarian function. Although the etiology of these symptoms is not clearly understood, it appears to be linked with the decline and imbalance of natural hormones, particularly the sex related hormones and more particularly to the decrease in the production of estrogens. Many symptoms have been linked to what is generally called, "the post-menopausal syndrome". These symptoms are often highly idiosyncratic and of varying severity and length of duration both between different patients as well as within the same patient. Many of the symptoms are serious and sometimes life-threatening pathologies, e.g., osteoporosis, hyperlipidemia, and type II diabetes. Some symptoms are less serious, but cause a great deal of pain and/or suffering, e.g., hot flashes, palpitations, atrophic vaginitis, joint pain, and muscular weakness. Yet other symptoms are of a psychological nature, e.g., headache, dizziness, lack of concentration, sleeplessness, apathy, lassitude, depression, and a sense of uselessness. The psychological symptoms are probably the most idiosyncratic of all in the post-menopausal syndrome and the least understood. Many have argued that there is no post-menopausal syndrome as a true psychiatric syndrome, but it is undeniable that these are common in post-menopausal women and make their appearance at the onset of menopause. It is not clear whether these psychological symptoms are the direct effect of estrogen deprivation in the central or peripheral nervous system or if the symptoms are the result of the vasomotor effects of estrogen deprivation, e.g., hot flashes which disturb sleep may cause the tiredness and the apathy so often seen.
The subject of this invention deals with the treatment of the vasomotor and psychological symptoms associated with menopause. The major and most common vasomotor symptom is hot flashes and/or flushes and the resulting sweats. Hot flashes are embarrassing, uncomfortable, and disturb the ability to sleep. A somewhat less common symptom is the palpitation of the heart rhythm, which although usually not pathological, can be very frightening and a cause of discomfort. The least common vasomotor symptoms are those of joint pain and muscular weakness. Additionally, the treatment of the associated psychological symptoms are the subject of this invention, although it not clear if this treatment is due to a direct impact on the nervous system or an indirect effect of the treatment of the vasomotor abnormalities.
There is currently only one approved method for the treatment of the above mentioned symptoms for post-menopausal women and that is the administration of exogenous estrogens or hormone replacement therapy. Although this therapy is very effective, it does entail some serious liabilities. The most serious liability associated with the administration of estrogens is the threat of endometrial cancer, and as a result, a progestinal agent must be given either along with or serially with the estrogen to reduce this risk. The inclusion of a progestin in a hormone replacement protocol makes such a regiment unattractive to a majority of women due to the progestin's negative psychological side-effects. Additionally, the added progestins can negate some of the positive effects of the estrogens, e.g., the control of hyperlipidemia. Many women do not like other side-effects of a hormone replacement therapy, e.g., the resumption of menses, weight gain, and tenderness of breast tissue. The overall result is that while hormone replacement therapy is effective in treating many of the vasomotor and psychological symptoms associated with the menopause, there is poor patient compliance. Ideally, a better treatment for these symptoms would be useful.
The pharmacological effects of the hormones such as estrogen are poorly understood and often contradictory in many, cases, e.g., in endometriosis which is caused by an inappropriate response of certain tissues to estrogen, can in some cases be treated by estrogen administration, yet in others treated by the administration of androgens. It is often unclear what the particular response to a hormone will be in the treatment of a disease and therefore each disease must be investigated on a case by case basis.
The molecular mechanism of how the steroid hormone works is somewhat better understood, in that it is known that the hormone binds to a specific receptor in the cellular cytosol. The hormone-receptor complex is translocated to the nucleus of the target cell where it regulates gene function. Therefore, it can be said that the hormone is a gene regulatory molecule. It is not known exactly which genes are activated or suppressed in the cell or whether the same hormone operates the same way in each target cell. It is probably this lack of knowledge which creates the myriad of surprising and contradictory effects which all hormones display in their pharmacology.